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Purpose: Automated treatment planning for multiple brain metastases differs from traditional planning approaches. It is therefore helpful to understand which parameters for optimization are available and how they affect the plan quality. This study aims to provide a reference for designing multi-metastases treatment plans and to define quality endpoints for benchmarking the technique from a scientific perspective., Methods: In all, 20 patients with a total of 183 lesions were retrospectively planned according to four optimization scenarios. Plan quality was evaluated using common plan quality parameters such as conformity index, gradient index and dose to normal tissue. Therefore, different scenarios with combinations of optimization parameters were evaluated, while taking into account dependence on the number of treated lesions as well as influence of different beams., Results: Different scenarios resulted in minor differences in plan quality. With increasing number of lesions, the number of monitor units increased, so did the dose to healthy tissue and the number of interlesional dose bridging in adjacent metastases. Highly modulated cases resulted in 4-10% higher V 10% compared to less complex cases, while monitor units did not increase. Changing the energy to a flattening filter free (FFF) beam resulted in lower local V 12Gy (whole brain-PTV) and even though the number of monitor units increased by 13-15%, on average 46% shorter treatment times were achieved., Conclusion: Although no clinically relevant differences in parameters where found, we identified some variation in the dose distributions of the different scenarios. Less complex scenarios generated visually more dose overlap; therefore, a more complex scenario may be preferred although differences in the quality metrics appear minor., (© 2024. The Author(s).)

Stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) is a very rare autoinflammatory disease related to STING1 mutation. SAVI is mainly characterized by fever attacks and skin and respiratory manifestations such as interstitial lung disease or alveolar hemorrhage. Respiratory involvement occurs in 80% of cases and might progress to severe lung fibrosis and require lung transplantation (LT). Three patients with SAVI who underwent LT have been reported to date. Two of the three patients died months or years after LT due to multiple organ failure or sepsis. However, the diagnosis of SAVI was made after LT, thus preventing the use of targeted therapy, such as the Janus kinase 1 and 2 inhibitor (JAK1/2i) ruxolitinib, which might be beneficial for the respiratory status of these patients. We aimed to report our experience in managing three patients who were followed in three large lung transplantation centers in France and who benefited from ruxolitinib before undergoing LT. We describe posttransplant complications that occurred as well as outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator ( CFTR ) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response., Methods: CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (Δ I ETI/DMSO %WT)., Results: 11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). Δ I ETI/DMSO %WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI., Conclusions: Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication., Competing Interests: Conflict of interest: P.R. Burgel reports grants from Vertex and GSK, outside the submitted work. N. Stremler reports advisory board participation with Vertex, outside the submitted work. B. Douvry reports grants and advisory board participation with Vertex, outside the submitted work. L. Le Clainche reports payment for expert testimony from Zambon, Novartis and Viatris, outside the submitted work. C. Marguet reports consulting fees from Vertex and Mylan, and payment for expert testimony from Vertex and Zambon, outside the submitted work. P. de Carli reports grants from Vaincre la Mucoviscidose, outside the submitted work. I. Sermet-Gaudelus reports support for the present manuscript from Vaincre la Mucoviscidose and Mucoviscidose ABCF2. I. Sermet-Gaudelus also reports, outside the submitted work, grants from Agence Nationale pour la Recherche, Assistance Publique–Hôpitaux de Paris and Vertex Innovation Award, and consulting fees and travel support from Vertex therapeutics. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: Biological disease-modifying anti-rheumatic drugs (bDMARDs) targeting interleukin (IL)-6 and IL-1β represent a steroid-sparing first-line therapy used in systemic-onset juvenile idiopathic arthritis (sJIA). Recently, the occurrence of pulmonary alveolar proteinosis (PAP) in sJIA patients was reported with early-onset and exposure to bDMARDs as potential risk factors. We report on a new case with longitudinal immunomonitoring successfully treated by Janus Kinase inhibitors (JAKi) and review past clinical descriptions of this new entity., Methods: We report one case of pulmonary alveolar proteinosis and macrophage activation syndrome (PAP-MAS) with longitudinal immunomonitoring. We then conducted a review of the literature of seven publications reporting 107 cases of PAP-MAS sJIA, and included the main characteristics and evolution under treatment., Results: Of the seven articles analyzed, the incidence of PAP-MAS among sJIA patients varied from 1.28% to 12.9%. We report here a single case among a cohort of 537 sJIA patients followed in the pediatric department of the Hospices Civils de Lyon over the last 15 years. This child presented with all clinical and immunological characteristics of PAP-MAS. After several lines of treatment, he benefited from JAKi and improved with respect to both systemic symptoms and lung disease. In the literature, strategies with monoclonal antibodies targeting either INF-γ or IL-1β/IL-18 have been tested with variable results. Orally taken JAKi presents the advantage of targeting multiple cytokines and avoiding parenteral injections of monoclonal antibodies that may contribute to the pathogenesis., Conclusions: JAKi represent a promising option in the treatment of lung disease associated with sJIA.

Introduction: Natalizumab, a therapy for relapsing-remitting multiple sclerosis (RRMS), is associated with a risk of progressive multifocal leukoencephalopathy (PML). Over the last several years, practitioners have used off-label extended interval dosing (EID) of natalizumab to reduce PML risk, despite the absence of a large-scale efficacy evaluation., Methods: We conducted a retrospective, multicenter cohort study among adults with RRMS receiving stable standard interval dosing (SID), defined as a ≥ 12-month consecutive period of ≥ 11 natalizumab infusions/year in France. We compared the 12-month risk difference of remaining relapse-free (primary endpoint) between patients who switched to EID (≤ 9 natalizumab infusions) and those who remained on SID, with a noninferiority margin of - 11%. We used propensity score methods such as inverse probability treatment weighting (IPTW) and 1:1 propensity score matching (PSM). Secondary endpoints were annualized relapse rate, disease progression, and safety., Results: Baseline characteristics were similar between patients receiving EID (n = 147) and SID (n = 156). The proportion of relapse-free patients 12 months postbaseline was 142/147 in the EID (96.6%) and 144/156 in the SID group (92.3%); risk difference (95% CI) 4.3% (- 1.3 to 9.8%); p < 0.001 for non-inferiority. There were no significant differences between relapse rates (0.043 vs. 0.083 per year, respectively; p = 0.14) or Expanded Disability Status Scale mean scores (2.43 vs. 2.72, respectively; p = 0.18); anti-JC virus index values were similar (p = 0.23); and no instances of PML were reported. The comparisons using IPTW (n = 306) and PSM (n = 204) were consistent., Conclusion: These results support the pertinence of using an EID strategy for RRMS patients treated with natalizumab., Clinical Trials: gov identifier (NCT04580381)., (© 2023. The Author(s).)

Background: Prostate-specific antigen (PSA)-based detection of prostate cancer (PCa) often leads to negative biopsy results or detection of clinically insignificant PCa, more frequently in the PSA range of 2-10 ng/ml, in men with increased prostate volume and normal digital rectal examination (DRE)., Objective: This study evaluated the accuracy of Proclarix, a novel blood-based diagnostic test, to help in biopsy decision-making in this challenging patient population., Design, Setting, and Participants: Ten clinical sites prospectively enrolled 457 men presenting for prostate biopsy with PSA between 2 and 10 ng/ml, normal DRE, and prostate volume ≥35 cm 3 . Transrectal ultrasound-guided and multiparametric magnetic resonance imaging (mpMRI)-guided biopsy techniques were allowed., Outcome Measurements and Statistical Analysis: Serum samples were tested blindly at the end of the study. Diagnostic performance of Proclarix risk score was established in correlation to systematic biopsy outcome and its performance compared with %free PSA (%fPSA) and the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator (RC) as well as Proclarix density compared with PSA density in men undergoing mpMRI., Results and Limitations: The sensitivity of Proclarix risk score for clinically significant PCa (csPCa) defined as grade group (GG) ≥2 was 91% (n = 362), with higher specificity than both %fPSA (22% vs 14%; difference = 8% [95% confidence interval {CI}, 2.6-14%], p = 0.005) and RC (22% vs 15%; difference = 7% [95% CI, 0.7-12%], p = 0.028). In the subset of men undergoing mpMRI-fusion biopsy (n = 121), the specificity of Proclarix risk score was significantly higher than PSA density (26% vs 8%; difference = 18% [95% CI, 7-28%], p < 0.001), and at equal sensitivity of 97%, Proclarix density had an even higher specificity of 33% [95% CI, 23-43%]., Conclusions: In a routine use setting, Proclarix accurately discriminated csPCa from no or insignificant PCa in the most challenging patients. Proclarix represents a valuable rule-out test in the diagnostic algorithm for PCa, alone or in combination with mpMRI., Patient Summary: Proclarix is a novel blood-based test with the potential to accurately rule out clinically significant prostate cancer, and therefore to reduce the number of unneeded biopsies., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Several benefits have been reported after applying the principles of enhanced recovery after surgery (ERAS) into the perioperative care of patients undergoing robot-assisted radical prostatectomy (RARP). Nevertheless, there are still barriers. We aimed to identify the key areas by systematically surveying urology departments in Germany and Austria. A 27-question survey on the adoption of ERAS principles for the perioperative care of RARP patients was designed, in compliance with the guidelines on good practice in conducting and reporting of survey research. After positive testing for face and content validity, the survey was distributed via postal mail to 82 departments performing RARP. In total, 39 departments responded to our survey (response rate 48%). The ERAS adoption rates ranged from 21 to 97%, with nine ERAS principles being widely adopted (72-92% of the departments). The lowest adoption rates and, subsequently, the largest potential for optimization were detected for the preoperative nutrition counselling (21%), preoperative pelvic floor physiotherapy (54%), postoperative early initiation of nutrition (44%) and postoperative patient audit for further quality improvement (36%). High-volume centers performed more frequently a perioperative nutrition counselling (8/27; 30%) than low-volume centers (0/12; 0%; p = 0.036). The implementation of the ERAS principles into the perioperative care algorithm were medium-to-high, yet not optimal. Our real-world data assessment revealed four key areas showing low adoption rates (nutrition counselling, preoperative pelvic floor physiotherapy, early initiation of nutrition and patient audit), implying a great potential for further optimization., (© 2021. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)